Project Summary Prediabetes is an age-associated condition where glucose levels are not high enough to be diagnosed as diabetes and is an important risk factor for the development of type 2 diabetes (T2D), cardiovascular disease, kidney disease and stroke. Compelling evidence supports that oxidative stress and mitochondrial dysfunction contribute significantly to the development of insulin resistance (IR). Activation of the renin- angiotensin system (RAS) results in IR and T2D in part through the increased production of mitochondrial radical oxygen species (mtROS) that may selectively damage mitochondrial DNA (mtDNA) and increase mitochondrial dysfunction. Thus, mitochondrial dysfunction may play a role in the onset of prediabetes. In rodents inhibition of RAS ameliorates mitochondrial dysfunction. However, the molecular mechanisms of RAS inhibition by angiotensin receptor (AT1) blockers on precluding prediabetes in humans remain unknown. We show that losartan significantly decreases insulin levels in prediabetic rhesus monkeys and glucose levels in healthy/non-diabetic monkeys after 12 months of treatment. Thus, losartan is exerting beneficial effects in both prediabetic and healthy middle-aged rhesus monkeys. In addition, our results show that healthy middle-age monkeys exhibit increased levels of nDNA damage compared with young animals, and that treatment with losartan significantly reduces lesion numbers to levels similar to young animals. These findings suggest that losartan reverses the effects of aging on nuclear DNA damage. We will test the hypothesis that inhibition of RAS reverses prediabetes by stimulating the insulin signaling pathway and by preventing mitochondrial damage and mitochondrial dysfunction. To test our hypothesis we will use skeletal muscle and adipose tissue from middle-age prediabetic rhesus monkeys (Macaca mulatta). This study may uncover mechanisms to delay or prevent IR/T2D and will focus on a potential paradigmatic change in the current clinical application of RAS blockade early in the prodromal phase of T2D.